Novel lncRNA-prader willi/angelman region RNA, SNRPN neighbour (PWARSN) aggravates tubular epithelial cell pyroptosis by regulating TXNIP via dual way in diabetic kidney disease

  • Cell Prolif. 2022 Oct 31;e13349. doi: 10.1111/cpr.13349.
Yi Song  1  2  3 ,  Feng Guo  1  2  3 ,  Yan-Yan Zhao  1 ,  Xiao-Jun Ma  1 ,  Li-Na Wu  1 ,  Ji-Feng Yu  4 ,  Hong-Fei Ji  1 ,  Ming-Wei Shao  1 ,  Feng-Juan Huang  1 ,  Lin Zhao  1 ,  Xun-Jie Fan  1  2  3 ,  Ya-Nan Xu  1  3 ,  Qing-Zhu Wang  5 ,  Gui-Jun Qin  1
Affiliations
  • 1. Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2. Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 3. Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou university, Zhengzhou, China.
  • 4. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 5. Department of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
PMID: 36316968 DOI: 10.1111/cpr.13349
Abstract

Objectives: Elevated thioredoxin-interacting protein (TXNIP)-induced Pyroptosis contributes to the pathology of diabetic kidney disease (DKD). However, the molecular mechanisms in dysregulated TXNIP in DKD remain largely unclear.

Materials and methods: Transcriptomic analysis identified a novel long noncoding RNA-Prader Willi/Angelman region RNA, SNRPN neighbour (PWARSN)-which was highly expressed in a proximal tubular epithelial cell (PTEC) under high glucose conditions. We focused on revealing the functions of PWARSN in regulating TXNIP-mediated Pyroptosis in PTECs by targeting PWARSN expression via lentivirus-mediated overexpression and CRISPR-Cas9-based knockout in vitro and overexpressing PWARSN in the renal cortex by AAV-9 targeted injection in vivo. A number of molecular techniques disclosed the mechanisms of PWARSN in regulating TXNIP induced-pyroptosis in DKD.

Results: TXNIP-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and PTEC Pyroptosis were activated in the renal tubules of patients with DKD and in diabetic mice. Then we explored that PWARSN enhanced TXNIP-driven PTECs Pyroptosis in vitro and in vivo. Mechanistically, cytoplasmic PWARSN sponged miR-372-3p to promote TXNIP expression. Moreover, nuclear PWARSN interacted and facilitated RNA binding motif protein X-linked (RBMX) degradation through ubiquitination, resulting in the initiation of TXNIP transcription by reducing H3K9me3-enrichment at the TXNIP promoter. Further analysis indicated that PWARSN might be a potential biomarker for DKD.

Conclusions: These findings illustrate distinct dual molecular mechanisms for PWARSN-modulated TXNIP and PTECs Pyroptosis in DKD, presenting PWARSN as a promising therapeutic target for DKD.

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